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Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors.

ABSTRACT: Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p?p?The Oncologist 2017;22:165-172Implications for Practice: Clinical trials in patients with advanced neuroendocrine tumors have used progression-free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression-free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.

SUBMITTER: Ter-Minassian M

PROVIDER: S-EPMC5330705 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors.

Ter-Minassian Monica M Zhang Sui S Brooks Nichole V NV Brais Lauren K LK Chan Jennifer A JA Christiani David C DC Lin Xihong X Gabriel Sylvie S Dinet Jérôme J Kulke Matthew H MH

The oncologist 20170208 2

Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received tre ...[more]

PMID: 28179574

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Project description:Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Project description:Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; p = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.

Project description:BackgroundOver the last few decades, the annual global incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has steadily increased. Because of the complex and inconsistent treatment of GEP-NETs, the prognosis of patients with GEP-NETs is still difficult to assess. The study aimed to construct and validate the nomograms included treatment data for prediction overall survival (OS) in GEP-NETs patients.MethodsGEP-NETs patients determined from the Surveillance, Epidemiology, and End Results (SEER)-13 registry database (1992-2018) and with additional treatment data from the SEER-18 registry database (1975-2016). In order to select independent prognostic factors that contribute significantly to patient survival and can be included in the nomogram, multivariate Cox regression analysis was performed using the minimum value of Akaike information criterion (AIC) and we analyzed the relationship of variables with OS by calculating hazard ratios (HRs) and 95% CIs. In addition, we also comprehensively compared the nomogram using to predict OS with the current 7th American Joint Committee on Cancer (AJCC) staging system.ResultsFrom 2004 to 2015, a total of 42,662 patients at diagnosis years with GEP-NETs were determined from the SEER database. The results indicated that the increasing incidence of GEP-NETs per year and the highest incidence is in patients aged 50-54. After removing cases lacking adequate clinicopathologic characteristics, the remaining eligible patients (n=7,564) were randomly divided into training (3,782 patients) and testing sets (3,782 patients). In the univariate analysis, sex, age, race, tumor location, SEER historic stage, pathology type, TNM, stage, surgery, radiation, chemotherapy, and CS tumor size were found to be significantly related to OS. Ultimately, the key factors for predicting OS were determined, involving sex, age, race, tumor location, SEER historic stage, M, N, grade, surgery, radiation, and chemotherapy. For internal validation, the C-index of the nomogram used to estimate OS in the training set was 0.816 (0.804-0.828). For external validation, the concordance index (C-index) of the nomogram used to predict OS was 0.822 (0.812-0.832). In the training and testing sets, our nomogram produced minimum AIC values and C-index of OS compared with AJCC stage. Decision curve analysis (DCA) indicated that the nomogram was better than the AJCC staging system because more clinical net benefits were obtained within a wider threshold probability range.ConclusionA nomogram combined treatment data may be better discrimination in predicting overall survival than AJCC staging system. We highly recommend to use our nomogram to evaluate individual risks based on different clinical features of GEP-NETs, which can improve the diagnosis and treatment outcomes of GEP-NETs patients and improve their quality of life.

Project description:BackgroundEverolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.MethodsWe randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.ResultsThe median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).ConclusionsEverolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Dataset Information

Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors.

Publications

Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors.

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